Candidate: Dr. Goff completed postgraduate training in 1985 and started the Schizophrenia Program of the Massachusetts General Hospital (MGH) with an NIMH "Faculty Scholar Award in Schizophrenia" in 1988. He is currently Director of the Freedom Trail Clinic and the MGH Schizophrenia Research Program. His receipt of a K24 award in 2001 allowed him to reduce clinical and administrative effort from 30 hour/week to 10 hours/week. During the period of the award he has mentored nine fellows and eight junior faculty members, while continuing to build an integrated translational research program focused on the development of glutamatergic agents utilizing pharmacology, neuroimaging, genetics and cognitive behavioral therapy (CBT). Environment: Dr. Goff s group has ample space and access to schizophrenia subjects at the Freedom Trail Clinic and a network of mental health clinics for recruitment of research subjects in the greater Boston area. He works closely with the MGH Neuroimaging group, the MGH Biostatistics Unit, the MGH Amino Acid Laboratory, the MGH/ Partners Genetics Research Program, and the Harvard/MIT Broad Institute for Genomics Research. Dr. Goff also has full access to the MGH General Clinical Research Center and Laboratory. Dr. Goff has full institutional commitment from Dr. Jerrold Rosenbaum (Chief of Psychiatry, MGH) ensuring protected time and resources to accomplish research and mentoring goals. Research: Dr. Goff's research plan involves continuation of his study of glutamatergic agents in schizophrenia. He will devote the period of the career development award to the problem of tachyphylaxis with agents acting at the glycine site of the NMDA receptor, including characterizing cognitive effects of single dose administration and repeated dosing following a frequency of administration designed to minimize tolerance. He will also study agents that target intracellular pathways "downstream" of the NMDA receptor to avoid tolerance formation. Finally, he will pursue, in first episode patients, promising results from a large add-on trial with lamotrigine (an inhibitor of glutamate release with neuroprotective properties). As effective pharmacologic approaches are developed, he will utilize genetics and neuroimaging as biomarkers and predictors of response, and will combine CBT with cognitive enhancing agents to maximize functional and symptomatic improvement. Dr. Goff will also continue his mentoring activities as he guides the career development of junior faculty researchers in his group as well as residents and research fellows working on research projects under his direction.